The present invention relates to novel potent PPAR-alpha-activating compounds for treating, for example, coronary heart disease, and to their preparation.
In spite of many successful therapies, coronary heart disease (CHD) remains a serious public health problem. Treatment with statins, which inhibit HMG-CoA reductase, successfully lowers both LDL cholesterol plasma concentrations and the mortality of patients at risk; however, convincing treatment strategies for the therapy of patients having an unfavourable HDL/LDL cholesterol ratio or hypertriglyceridaemia are still not available to date.
Currently, fibrates are the only therapy option for patients of these risk groups. They act as weak agonists of the peroxisome-proliferator-activated receptor (PPAR)-alpha (Nature 1990, 347, 645-50). A disadvantage of the fibrates which have hitherto been approved is that their interaction with the receptor is only weak, requiring high daily doses and causing considerable side-effects.
WO 00/23407 describes PPAR modulators for treating obesity, atherosclerosis and/or diabetes.
It was an object of the present invention to provide novel compounds which can be used as PPAR-alpha modulators.
It has now been found that this object is achieved by compounds of the general formula (I) 
in which
A represents a bond or represents a xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94 group,
X represents O, S or CH2,
R1, R2 and R3 are identical or different and independently of one another each represents hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C6)-alkoxy, (C6-C10)-aryloxy, halogen, trifluoromethyl, trifluoromethoxy, (C1-C6)-alkylaminosulphonyl, nitro or cyano,
or
R1 and R2 are attached to two adjacent carbon atoms and together with these form a fused cyclohexane or benzene ring, the latter optionally being substituted by a (C1-C4)-alkylsulphonylmethyl group,
and
R3 is as defined above,
R4 represents hydrogen or (C1-C4)-alkyl,
R5 and R6 represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group,
R7 represents hydrogen, (C1-C6)-alkyl, phenyl or benzyl, where the aromatic radicals mentioned for their part may in each case be mono- to trisubstituted by identical or different substituents from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, hydroxyl and halogen,
R8 represents hydrogen, (C6-C10)-aryl or represents (C1-C4)-alkyl which for its part may be substituted by hydroxyl, trifluoromethoxy, (C1-C4)-alkoxy or phenoxy, which for their part are optionally mono- or disubstituted by trifluoromethyl, or by (C6-C10)-aryl or 5- or 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, where all aryl and hetaroaryl rings mentioned may for their part in each case be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino,
R9 and R10 are identical or different and independently of one another each represents hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy or halogen,
R11 and R12 are identical or different and independently of one another each represents hydrogen or (C1-C6)-alkyl or together with the carbon atom to which they are attached form a (C4-C7)-cycloalkyl ring,
and
R13 represents hydrogen or represents a group which can hydrolysed and degraded to the corresponding carboxylic acid,
and their pharmaceutically acceptable salts, hydrates and solvates,
which have pharmacological action and can be used as medicaments or for preparing medicament formulations.
In the context of the invention, a hydrolysable group in the definition of R13 is a group which, in particular in the body, leads to a conversion of the xe2x80x94C(O)OR13 grouping into the corresponding carboxylic acid (R13=hydrogen). Such groups are, by way of example and by way of preference: benzyl, (C1-C6)-alkyl or (C3-C8)-cycloalkyl which are in each case optionally mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, amino, (C1-C6)-alkoxy, carboxyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonylamino and (C1-C6)-alkanoyloxy, and in particular (C1-C4)-alkyl which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, amino, (C1-C4)-alkoxy, carboxyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkoxycarbonylamino and (C1-C4)-alkanoyloxy.
In the context of the invention, (C1-C6)-alkyl and (C1-C4)-alkyl represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, respectively. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl and tert-butyl.
In the context of the invention, (C6-C10)-aryl represents an aromatic radical having 6 to 10 carbon atoms. A preferred example is the aryl radical phenyl.
In the context of the invention, (C3-C8)-cycloalkyl and (C4-C7)-cycloalkyl represent a cycloalkyl group having 3 to 8 and 4 to 7 carbon atoms, respectively. The following radicals may be mentioned by way of example and by way of preference: cyclobutyl, cyclopentyl and cyclohexyl.
In the context of the invention, (C1-C6)-alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
In the context of the invention, (C6-C10)-aryloxy represents an aromatic radical having 6 to 10 carbon atoms which is attached via an oxygen atom. A preferred example is the aryloxy radical phenoxy.
In the context of the invention, (C1-C6)-alkoxycarbonyl represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms which is attached via a carbonyl group. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
In the context of the invention, (C1-C6)-alkoxycarbonylamino represents an amino group having a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 carbon atoms in the alkoxy radical and is attached via the carbonyl group. Preference is given to an alkoxycarbonylamino radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and tert-butoxycarbonylamino.
In the context of the invention, (C1-C6)-alkanoyloxy represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which carries a doubly attached oxygen atom in the 1-position and is attached in the 1-position via a further oxygen atom. The following radicals may be mentioned by way of example and by way of preference: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.
In the context of the invention, (C1-C6)-alkylamninosulphonyl represents an amino group which is attached via a sulphonyl group and has a straight-chain or branched alkyl substituent having 1 to 6 carbon atoms. Preference is given to an alkylaminosulphonyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methylaminosulphonyl, ethylaminosulphonyl, n-propylaminosulphonyl, isopropylaminosulphonyl and tert-butylaminosulphonyl.
In the context of the invention, halogen represents fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
In the context of the invention, 5- or 6-membered heteroaryl having up to 3 heteroatoms selected from the group consisting of S, N and O generally represents a monocyclic heteroaromatic radical which is attached via a ring carbon atom of the heteroaromatic radical, or, if appropriate, via a ring nitrogen atom of the heteroaromatic radical. The following radicals may be mentioned by way of example and by way of preference: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl. Preference is given to furanyl, thienyl and oxazolyl.
Depending on the substitution pattern, the compounds according to the invention can exist in stereoisomeric forms which are either like image and mirror image (enantiomers) or which are not like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform components.
Furthermore, certain compounds may be present in tautomeric forms. This is known to the person skilled in the art, and such compounds are likewise included within the scope of the invention.
The compounds according to the invention can also be present as salts. In the context of the invention, preference is given to physiologically acceptable salts.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with organic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid or to salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalene-disulphonic acid.
Physiologically acceptable salts can also be salts of the compounds according to the invention with bases, such as, for example, metal or ammonium salts. Preferred examples are alkali metal salts (for example sodium salts or potassium salts), alkaline earth metal salts (for example magnesium salts or calcium salts), and also ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, ethyldilsopropylamine, monoethanolamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.
Preference is given to compounds of the general formula (I),
in which
A represents a bond or represents a xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94 group,
X represents O, S or CH2,
R1, R2 and R3 are identical or different and independently of one another each represents hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano,
R4 represents hydrogen or (C1-C4)-alkyl,
R5 and R6 each represents hydrogen or together with the carbon atom to which they are attached form a carbonyl group,
R7 represents hydrogen, (C1-C6)-alkyl, phenyl or benzyl, in which the aromatic radicals mentioned for their part may in each case be mono- to trisubstituted by identical or different substituents from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, hydroxyl or halogen,
R8 represents hydrogen, (C6-C10)-aryl or (C1-C4)-alkyl, which for its part is optionally substituted by (C6-C10)-aryl or 5- or 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, where all of the ring systems mentioned may for their part in each case be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino,
R9 and R10 are identical or different and independently of one another each represents hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy or halogen,
R11 and R12 are identical or different and independently of one another each represents hydrogen or (C1-C6)-alkyl, or together with the carbon atom to which they are attached they form a (C4-C7)-cycloalkyl ring,
and
R13 represents hydrogen or a group that can be hydrolysed and degraded to the corresponding carboxylic acid,
and their pharmaceutically acceptable salts, hydrates and solvates.
Particular preference is given to compounds of the general formula (I),
in which
A represents a xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94 group,
X represents O, S or CH2,
R1, R2 and R3 are identical or different and independently of one another each represents hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, chlorine, fluorine, trifluoromethyl, trifluoromethoxy, nitro or cyano,
R4 represents hydrogen or methyl,
R5 and R6 each represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group,
R7 represents hydrogen, (C1-C4)-alkyl or benzyl,
R8 represents hydrogen, phenyl, benzyl or 5-membered heteroarylmethyl having up to two heteroatoms from the group consisting of N, O and S, where the aromatic ring systems mentioned for their part may in each case be mono- to trisubstituted by identical or different substituents from the group consisting of chlorine, fluorine, bromine, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, trifluoromethyl and amino,
R9 and R10 are identical or different and independently of one another each represents hydrogen, (C1-C3)-alkyl, (C1-C3)-alkoxy, trifluoromethyl, fluorine or chlorine,
R11 and R12 are identical or diffferent and independently of one another each represents hydrogen, methyl or ethyl, or together with the carbon atom to which they are attached they form a cyclopentyl or cyclohexyl ring,
and
R13 represents hydrogen or represents a group that can be hydrolysed and degraded to the corresponding carboxylic acid,
and their pharmaceutically acceptable salts, hydrates and solvates.
Very particular preference is given to compounds of the general formula (I),
in which
A represents a xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94 group,
X represents O, S or CH2,
R1 represents hydrogen, methyl or methoxy,
R2 and R3 are identical or different and independently of one another each represents methyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine,
R4 represents hydrogen,
R5 and R6 together with the carbon atom to which they are attached form a carbonyl group,
R7 represents methyl, ethyl, n-propyl or, in particular, hydrogen,
R8 represents phenyl, furanylmethyl or thienylmethyl, where the ring systems mentioned for their part may in each case be mono- or disubstituted by identical or different substituents from the group consisting of methyl and ethyl,
R9 and R10 are identical or different and each represents hydrogen or methyl in particular hydrogen,
R11 and R12 are identical or different and each represents hydrogen or methyl in particular methyl,
and
R13 represents a group which can be hydrolysed and degraded to the corresponding carboxylic acid, or, in particular, represents hydrogen,
and their pharmaceutically acceptable salts, hydrates and solvates.
The general or preferred radical definitions listed above apply both to the end products of the formula (I) and, correspondingly, to the starting materials and intermediates required in each case for the preparation.
The individual radical definitions given in the respective combinations or preferred combinations of radicals are, independently of the respective given combination of radicals, also replaced by any radical definitions of other combinations.
Of particular importance are compounds of the formula (I) in which R4 is hydrogen.
Of particular importance are compounds of the formula (I) in which R5 and R6 together with the carbon atom to which they are attached form a carbonyl group.
Of particular importance are compounds of the formula (I) in which
R1 represents hydrogen, methyl or methoxy,
and
R2 and R3 are identical or different and independently of one another each represents methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine.
Of particular importance are compounds of the formula (I) in which
R8 represents phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, where the ring systems mentioned for their part may in each case be mono- or disubstituted by methyl, or represents 2-methoxyethyl.
Of very particular importance are compounds of the formula (IA) 
in which
A represents a xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94 group,
X represents O or S,
R1 represents hydrogen, methyl or methoxy,
R2 and R3 are identical or different and independently of one another each represents methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine,
and
R8 represents phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl, where the ring systems mentioned for their part may in each case be mono- or disubstituted by methyl, or represents 2-methoxyethyl.
Moreover, we have found a process for preparing the compounds of the general formula (I) according to the invention, characterized in that
[A] compounds of the general formula (II) 
in which
A, X, R7, R8, R9, R10, R11 and R12 are each as defined above
and
T represents benzyl, (C1-C6)-alkyl or a polymeric support suitable for solid-phase synthesis,
are initially, with activation of the carboxylic acid group in (II), reacted with compounds of the general formula (III) 
in which
R1, R2 and R3 are each as defined above,
to give compounds of the general formula (Ia) 
in which
A, X, T, R1, R2, R3, R7, R8, R9, R10, R11 and R12 are each as defined above,
or
[B] compounds of the general formula (IV) 
in which
A, X, T, R8, R9, R10, R11 and R12 are each as defined above, are, in the presence of a base, reacted with compounds of the general formula (V) 
in which
R1, R2, R3 and R7 are each as defined above
and
Q is a suitable leaving group, for example halogen, mesylate or tosylate, preferably bromine or iodine,
likewise to compounds of the general formula (Ia)
the compounds of the general formula (Ia) are, if appropriate according to known methods for amide alkylation or amide reduction, converted into compounds of the general formula (Ib) 
in which
A, X, T, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each as defined above
then converted with acids or bases into the corresponding carboxylic acids of the general formula (Ic) 
in which
A, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each as defined above,
and these are, if appropriate according to known methods for esterification, modified further by reaction with compounds of the general formula (VI)
R13xe2x80x94Zxe2x80x83xe2x80x83(VI), 
in which
R13 is as defined above
and
Z represents a suitable leaving group for example halogen, mesylate or tosylate or represents a hydroxyl group.
The process according to the invention is generally carried out at atmospheric pressure. However, it is also possible to carry out the process under elevated pressure or under reduced pressure (for example in a range of from 0.5 to 5 bar).
Solvents which are suitable for the process are customary organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, pyridine, dimethyl sulphoxide, dimethylformamide, N,Nxe2x80x2-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned.
Solvents which are preferred for process step (II)+(III)xe2x86x92(Ia) are dichloromethane and dimethylformamide. For process step (IV)+(V)xe2x86x92(Ia), preference is given to dimethylformamide.
The process step (II)+(III)xe2x86x92(Ia) according to the invention is generally carried out in a temperature range of from 0xc2x0 C. to +100xc2x0 C., preferably from 0xc2x0 C. to +40xc2x0 C. The process step (IV)+(V)xe2x86x92(Ia) is generally carried out in a temperature range of from 0xc2x0 C. to +120xc2x0 C., preferably from +50xc2x0 C. to +100xc2x0 C.
The auxiliaries used for the amide formation in process step (II)+(III)xe2x86x92(Ia) are preferably customary condensing agents, such as carbodiimides, for example, N,Nxe2x80x2-diethyl-, N,Nxe2x80x2-dipropyl-, N,Nxe2x80x2-diisopropyl-, N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminoisopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride (EDC), or carbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds, such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride or benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or O-(benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU), if appropriate in combination with further auxiliaries such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, and the bases used are preferably alkali metal carbonates, for example sodium carbonate or bicarbonate or potassium carbonate or bicarbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylethylamine. Particular preference is given to the combination of EDC, N-methylmorpholine and 1-hydroxybenzotriazole, of EDC, triethylamine and 1-hydroxybenzotriazole and of HATU and diisopropylethylamine.
Suitable bases for the reaction (IV)+(V)xe2x86x92(Ia) are the customary inorganic bases, such as alkali metal alkoxides, such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylethylamine. Preference is given to sodium bicarbonate.
The hydrolysis of the carboxylic acid esters in the process step (Ia) or (Ib)xe2x86x92(Ic) is carried out by customary methods by treating the esters in inert solvents with bases, the salts that are initially formed being converted by treatment with acid into the free carboxylic acids. In the case of the tert-butyl esters, the hydrolysis is preferably carried out using acids.
Suitable solvents for the hydrolysis of the carboxylic acid esters are water or the organic solvents which are customary for ester cleavage. These preferably include alcohols, such as methanol, ethanol, propanol, isopropanol or butanol, or ethers, such as tetrahydrofuran or dioxane, dimethylformamide, dichloromethane or dimethyl sulphoxide. It is also possible to use mixtures of the solvents mentioned. Preference is given to water/tetrahydrofuran and, in the case of the reaction with trifluoroacetic acid, to dichloromethane and, in the case of hydrogen chloride, to tetrahydrofuran, diethyl ether, dioxane or water.
Bases suitable for the hydrolysis are the customary inorganic bases. These preferably include alkali metal hydroxide or alkaline earth metal hydroxide, such as, for example, sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium bicarbonate. Particular preference is given to using sodium hydroxide or lithium hydroxide.
Suitable acids are, in general, trifluoroacetic acid, sulphuric acid, hydrogen chloride, hydrogen bromide and acetic acid, or mixtures thereof, if appropriate with addition of water. Preference is given to hydrogen chloride or trifluoroacetic acid in the case of the tert-butyl esters and to hydrochloric acid in the case of the methyl esters.
In the case of compounds of the general formula (Ia) or (Ib) prepared by solid-phase synthesis and attached to a polymeric support via the carboxylic acid group, the cleavage from the resin to give the compounds of the general formula (Ic) is likewise carried out by the above-described customary methods for carboxylic acid ester hydrolysis. Here, preference is given to using trifluoroacetic acid.
When carrying out the hydrolysis, the base or the acid is generally employed in an amount of from 1 to 100 mol, preferably from 1.5 to 40 mol, based on 1 mole of the ester.
The hydrolysis is generally carried out in a temperature range of from 0xc2x0 C. to +100xc2x0 C., preferably from 0xc2x0 C. to +50xc2x0 C.
The compounds of the general formula (II) are novel, and they can be prepared by initially
[a] reacting compounds of the general formula (VII) 
in which
X, T, R9, R10, R11 and R12 are each as defined above
and
B represents a bond or a methylene group
in the presence of a suitable reducing agent with compounds of the general formula (VIII)
xe2x80x83R14xe2x80x94NH2xe2x80x83xe2x80x83(VIII),
in which
R14 [a-1] has the meaning of R8 given above
or
[a-2] represents a group of the formula 
in which
R7 is as defined above
and
R15 represents (C1-C4)-alkyl or trimethylsilyl,
to give compounds of the general formula (IX) 
in which
B, X, T, R9, R10, R11, R12 and R14 are each as defined above,
then reacting these compounds in the presence of a base with compounds of the general formula (X)
xe2x80x83R16xe2x80x94Yxe2x80x83xe2x80x83(X),
in which
R16 in the case of process variant [a-1] represents a group of the formula 
in which R7 and R15 are each as defined above
or,
in the case of process variant [a-2] has the meaning of R8 given above and
Y represents a suitable leaving group, such as, for example halogen, mesylate or tosylate, preferably bromine or iodine,
to give compounds of the general formula (XI) 
in which
B, X, T, R7, R8, R9, R10, R11, R12 and R15 are each as defined above,
and finally selectively hydrolysing the carboxylic acid ester grouping xe2x80x94COOR15 in these compounds to the carboxylic acid,
or
[b] reacting compounds of the general formula (XII) 
in which
A, X, T, R9, R10, R11 and R12 are each as defined above
in the presence of a suitable reducing agent with compounds of the general formula (XIII)
R17xe2x80x94CHOxe2x80x83xe2x80x83(XIII), 
in which
R17 represents hydrogen, (C6-C10)-aryl, 5- or 6-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S, or represents (C1-C3)-alkyl which for its part may be substituted by hydroxyl, trifluoromethoxy, (C1-C4)-alkoxy or phenoxy, which for their part are optionally mono- or disubstituted by trifluoromethyl, or by (C6-C10)-aryl or 5- to 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, where all aryl and heteroaryl rings mentioned may for their part in each case be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino,
to give compounds of the general formula (XIV) 
in which
A, X, T, R9, R10, R11, R12 and R17 are each as defined above,
then reacting these compounds in the presence of a base with compounds of the general formula (XV) 
in which
R7, R15 and Y are each as defined above
to give compounds of the general formula (XVI) 
in which
A, X, T, R7, R9, R10, R11, R12, R15 and R17 are each as defined above,
and finally selectively hydrolysing the carboxylic acid ester grouping xe2x80x94COOR15 in these compounds to the carboxylic acid.
The entire process can also be carried out as solid-phase synthesis. In this case, the compounds of the general formula (VII) or (XII) are attached as carboxylic acid esters to a suitable support resin, the further reactions are carried out on solid phase and the target compound is finally cleaved off from the resin. Solid-phase synthesis and the attachment and the cleavage from the resin are customary standard techniques. To mention but one example from the extensive literature, reference is made to the publication xe2x80x9cLinkers for Solid Phase Organic Synthesisxe2x80x9d, Ian W. James, Tetrahedron 55, 4855-4946 (1999).
The reaction (VII)+(VIII)xe2x86x92(IX) or (XII)+(XIII)xe2x86x92(XIV) is carried out in the solvents which are customary for reductive amination and inert under the reaction conditions, if appropriate in the presence of an acid. The solvents include, for example, water, dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane, or alcohols such as methanol, ethanol, propanol, isopropanol or butanol; it is also possible to use mixtures of the solvents mentioned. Preference is given to methanol and ethanol in each case with addition of acetic acid.
Suitable reducing agents for the reaction (VII)+(VIII)xe2x86x92(IX) or (XII)+(XIII)xe2x86x92(XIV) are complex aluminium hydrides or boron hydrides, such as, for example, diisobutylaluminium hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or tetrabutylammonium borohydride, or else catalytic hydrogenation in the presence of transition metal catalysts such as, for example, palladium, platinum, rhodium or Raney nickel. Preferred reducing agents are sodium cyanoborohydride, sodium triacetoxyborohydride and tetrabutylammonium borohydride.
The reaction (VII)+(VIII)xe2x86x92(IX) or (XII)+(XIII)xe2x86x92(XIV) is generally carried out in a temperature range of from 0xc2x0 C. to +40xc2x0 C.
The reaction (IX)+(X)xe2x86x92(XI) or (XIV)+(XV)xe2x86x92(XVI) is carried out in the customary solvents which are inert under the reaction conditions. Preference is given to dimethylformamide, tetrahydrofuran and dioxane.
Suitable bases for the reaction (IX)+(X)xe2x86x92(XI) or (XIV)+(XV)xe2x86x92(XVI) are the customary inorganic or organic bases. Preference is given to triethylamine.
The reaction (IX)+(X)xe2x86x92(XI) or (XIV)+(XV)xe2x86x92(XVI) is generally carried out in a temperature range of from 0xc2x0 C. to +100xc2x0 C.
The reaction (XI)xe2x86x92(II) or (XVI)xe2x86x92(II) is carried out in the solvents which are customary for ester cleavage and inert under the reaction conditions. In the case of the ester hydrolysis, these are preferably tetrahydrofuran, dioxane and alcohols, such as methanol and ethanol, in each case in a mixture with water. In the case of the cleavage of silyl esters, preference is given to using dioxane or tetrahydrofuran.
Suitable bases for the reaction (XI)xe2x86x92(II) or (XVI)xe2x86x92(II) are, in the case of the hydrolysis, the customary inorganic bases. Preference is given to lithium hydroxide, sodium hydroxide and potassium hydroxide. In the case of the cleavage of silyl esters, preference is given to using tetrabutylammonium fluoride.
The reaction (XI)xe2x86x92(II) or (XVI)xe2x86x92(II) is generally carried out in a temperature range of from 0xc2x0 C. to +100xc2x0 C.
The compounds of the general formula (IV) correspond to the compounds of the general formula (IX) or (XIV) and can be prepared as described above.
The compounds of the general formulae (III), (V), (VI), (VII), (VIII), (X), (XII), (XIII) and (XV) are commercially available, known or can be prepared by customary methods [cf., for example, P. J. Brown et al., J. Med. Chem. 42, 3785-88 (1999)].
The compounds of the formula (I) according to the invention have a surprising and useful spectrum of pharmacological activity and can therefore be used as versatile medicaments. In particular, they are suitable for treating coronary heart diseases, for the prophylaxis of myocardial infarction and for the treatment of restenosis after coronary angioplasty or stenting. The compounds of the formula (I) according to the invention are preferably suitable for treating arteriosclerosis and hypercholesterolaemia, for increasing pathogenically low HDL levels and for lowering elevated triglyceride, fibrinogen and LDL levels. In addition, they can be used for treating obesity, diabetes, for treating the metabolic syndrome (glucose intolerance, hyperinsulinaemia, dyslipidaemia and high blood pressure owing to insulin resistance), hepatic fibrosis and cancer.
The activity of the compounds according to the invention can be examined, for example, in vitro by the transactivation assay described in the experimental section.
The activity of the compounds according to the invention in vivo can be examined, for example, by the tests described in the experimental section.
Suitable administration forms for administering the compounds of the general formula (I) are all customary administration forms, i.e. oral, parenteral, inhalative, nasal, sublingual, rectal or external, for example transdermal, preferably oral or parenteral, administration forms. In the case of parenteral administration, particular mention has to be made of intravenous, intramuscular and subcutaneous administration, for example as a subcutaneous depot. Very particular preference is given to oral administration.
Here, the active compounds can be administered on their own or in the form of preparations. Preparations suitable for oral administration are, inter alia, tablets, capsules, pellets, sugar-coated tablets, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. Here, the active compound has to be present in such an amount that a therapeutic effect is obtained. In general, the active compound can be present in a concentration of from 0.1 to 100% by weight, in particular from 0.5 to 90% by weight, preferably from 5 to 80% by weight. In particular, the concentration of active compound should be 0.5-90% by weight, i.e. the active compound should be present in amounts sufficient to reach the dosage range stated.
To this end, the active compounds can be converted in a manner known per se into the customary preparations. This is carried out using inert non-toxic pharmaceutically suitable excipients, auxiliaries, solvents, vehicles, emulsifiers and/or dispersants.
Auxiliaries which may be mentioned are, for example: water, non-toxic organic solvents, such as, for example, paraffins, vegetable oils (for example sesame oil), alcohols (for example ethanol, glycerol), glycols (for example polyethylene glycol), solid carriers, such as natural or synthetic ground minerals (for example talc or silicates), sugar (for example lactose), emulsifiers, dispersants (for example polyvinylpyrrolidone) and glidants (for example magnesium sulphate).
In the case of oral administration, the tablets may, of course, also contain additives such as sodium citrate, together with additives such as starch, gelatine and the like. Aqueous preparations for oral administration may furthermore comprise flavour improvers or colorants.
In the case of oral administration, preference is given to administering dosages of from 0.001 to 5 mg/kg, preferably from 0.005 to 3 mg/kg, of body weight per 24 hours.
The embodiments below illustrate the invention. The invention is not limited to the examples.
The following abbreviations used represent: